Only in very rare cases a pharmaceutically active ingredient (API) is prescribed or administered to a patient as such, i.e. without any excipients and additives, respectively. In the vast majority of cases APIs that are intended for being used to treat subjects suffering from a certain disease are present in a pharmaceutical composition, together with specific excipients, and are formulated into suitable dosage forms. The excipients are added in order to confer specific, desired properties to the pharmaceutical composition/dosage form comprising the API.
When choosing excipients, possible interactions between the API(s) and the excipient(s) that may have a negative influence on the performance or properties of the pharmaceutical composition or dosage form have to be taken into account. For instance, it may be that certain excipients, in combination with certain APIs, in particular APIs that easily induce tableting trouble, lead to troubles during formulating the respective dosage form such as a tablet (“tableting trouble”). These tableting troubles mainly occur during the production of the tablets, i.e. during the tableting step.
With this respect, various methods for avoiding or minimizing tableting trouble have been disclosed, for instance increasing the amount of magnesium stearate used as lubricant or elongating the mixing time of the various ingredients of the pharmaceutical composition and tablet, respectively.
Further with this respect, WO 2008/093878 A1 discloses a tablet comprising a granule and a tableting aid, wherein the granule comprises an API that easily induces tableting trouble and microcrystalline cellulose, and the tableting aid comprises magnesium stearate and microcrystalline cellulose.
However, increasing the amount of excipients (such as magnesium stearate) or elongating the mixing time may result in problems with regard to quality or impaired producibility. Additionally, the more excipients (in terms of amount) being present in a pharmaceutical composition or dosage form such as a tablet, the bigger in size the dosage form (e.g. tablet), while at the same time maintaining the API dose. This, in turn, results in a decreased patients' acceptance. If, on the other hand, the size of the dosage from is maintained, less API can be present in said dosage form. The amount of the respective excipients being present in a pharmaceutical composition, and resulting from this amount the size of said pharmaceutical composition/dosage form, is of particular interest if there is not only one API, but two or more APIs that are to be formulated into the pharmaceutical composition/dosage form. This is for instance the case with regard to combination preparations (i.e. preparations that contain more than one API), such as preparations that are used in the treatment of diabetes.
The possibility of splitting the amount of microcrystalline cellulose and manufacturing the resulting parts of microcrystalline cellulose in different phases of the pharmaceutical composition (e.g. one part in the intragranulate phase, one part in the extragranulate phase) is a complex process that is time-consuming and cost-intensive. Additionally, the batch-size determining step in the manufacture of pharmaceutical compositions comprising a granulate phase is the granulation step. Thus, the more excipients are present in the intragranulate phase, the smaller the size of the manufactured batch.
Therefore, there is a need for an improved pharmaceutical composition, in particular solid oral dosage form such as a tablet, comprising an API that easily induces tableting trouble, in particular alogliptin or a pharmaceutically acceptable salt thereof, and a process for preparing the same.